US 12,331,069 B2
DOT1L degraders and uses thereof
Scott Armstrong, Wayland, MA (US); and Jun Qi, Sharon, MA (US)
Assigned to DANA-FARBER CANCER INSTITUTE, INC., Boston, MA (US)
Appl. No. 17/421,285
Filed by DANA-FARBER CANCER INSTITUTE, INC., Boston, MA (US)
PCT Filed Jan. 9, 2020, PCT No. PCT/US2020/012825
§ 371(c)(1), (2) Date Jul. 7, 2021,
PCT Pub. No. WO2020/146561, PCT Pub. Date Jul. 16, 2020.
Claims priority of provisional application 62/790,314, filed on Jan. 9, 2019.
Prior Publication US 2022/0048942 A1, Feb. 17, 2022
Int. Cl. C07H 19/16 (2006.01); A61P 35/02 (2006.01)
CPC C07H 19/16 (2013.01) [A61P 35/02 (2018.01)] 17 Claims
 
1. A compound of Formula (I):

OG Complex Work Unit Chemistry
or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein:
R8 is hydrogen, optionally substituted acyl, optionally substituted alkyl, or a nitrogen protecting group;
R9 is hydrogen, optionally substituted acyl, optionally substituted alkyl, or a nitrogen protecting group;
R10 is hydrogen, optionally substituted acyl, optionally substituted alkyl, or a nitrogen protecting group;
R11 is halogen, optionally substituted acyl, or optionally substituted alkyl;
each instance of R12 is independently hydrogen, optionally substituted acyl, or an oxygen protecting group;
L is

OG Complex Work Unit Chemistry
 and
lR indicates the point of attachment to D, and lA indicates the point of attachment to the moiety of formula

OG Complex Work Unit Chemistry
X is —CH2— or —O—;
ring B is an optionally substituted 5-10 membered heterocyclyl or optionally substituted 5-14 membered heteroaryl group;
n1 is 1, 2, 3, 4, 5, or 6;
n2 is 1, 2, 3, 4, 5, or 6;
n3 is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12;
g is 1, 2, 3, 4, 5, or 6; and
g1 is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and
D is of the formula IA or IB:

OG Complex Work Unit Chemistry
wherein:
for each set of two moieties A bound to the same carbon atom, one A is hydrogen, and the other A is one of:
(i) phenyl, optionally substituted with 1-5 substituents selected from the group consisting of —R1, —OR1, —NR1R2, —S(O)qR1, —SO2R1R2, —NR1SO2R2, —C(O)R1, —C(O)OR1, —C(O)NR1R2, —NR1C(O) R2, —NR1C(O)OR2, —CHF2, —CH2F, —CF3, and —OCF3;
(ii) naphthyl, optionally substituted with 1-5 substituents selected from the group consisting of —R1, —OR1, —NR1R2, —S(O)qR1, —SO2R1R2, —NR1SO2R2, —C(O) R1, —C(O)OR1, —C(O)NR1R2, —NR1C(O) R2, —NR1C(O)OR2, —CHF2, —CH2F, —CF3, and —OCF3;
(iii) a 5- or 6-membered monocyclic heteroaryl group, having 1-3 heteroatoms selected from the group consisting of O, N, and S, optionally substituted with 1-3 substituents selected from the group consisting of —R1, —OR1, —NR1R2, —S(O)qR1, —SO2R1R2, —NR1SO2R2, —C(O) R1, —C(O)OR1, —C(O)NR1R2, —NR1C(O) R2, —NR1C(O)OR2, —CHF2, —CH2F, —CF3, and —OCF3; and
(iv) an 8- to 10-membered bicyclic heteroaryl group containing 1-3 heteroatoms selected from the group consisting of O, N, and S, and having a first ring fused to a second ring through 3 to 4 carbon atoms, wherein the bicyclic heteroaryl group is optionally substituted with 1-3 substituents selected from the group consisting of —R1, —OR1, —NR1R2, —S(O)qR1, —SO2R1R2, —NR1SO2R2, —C(O) R1, —C(O)OR1, —C(O)NR1R2, —NR1C(O) R2, —NR1C(O)OR2, —CHF2, —CH2F, —CF3, and —OCF3;
Y is ═O, ═S, ═NR1, or ═CR1R2, R1 and R2 are each independently selected from the group consisting of hydrogen, nitro, hydroxyl, —COOH, —NH2, halogen, cyano, and C1-C14 alkyl optionally substituted with 1-3 substituents selected from the group consisting of C1-C14 alkyl, C1-C14 haloalkyl, C1-C14 alkoxy, nitro, hydroxyl, —COOH, —NH2, C1-C14 alkylamino, C1-C14 dialkylamino, halogen, and cyano;
R7 is hydrogen, optionally substituted C1-6 alkyl, or a nitrogen protecting group;
Z is selected from the group consisting of hydrogen, optionally substituted C1-C14 alkyl, optionally substituted C3-C10 cycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted alkyl-aryl, and —(CH2)p—K;
K is a 5- or 6-membered monocyclic heterocyclic or heteroaryl group containing 1-4 heteroatoms selected from the group consisting of O, N, and S, or an 8- to 10-membered bicyclic heteroaryl group containing 1-4 heteroatoms selected from the group consisting of O, N, and S;
p is an integer selected from the group consisting of 0, 1, 2, 3, and 4; and
q is an integer selected from the group consisting of 0, 1, 2, 3, and 4.